ABSTRACT Breast Cancer (BC) is the leading cause of cancer death for woman in the US. Breast cancer is treated by a combination of surgery, radiation, and various types of chemo and targeted therapeutic strategies. Approximately half of patients who have positive sentinel lymph nodes at surgery (and as many as 25% of patients who do not) eventually present with metastatic disease. Over 70% of BC patients eventually have skeletal involvement making bone the single most prevalent site of metastasis in BC. BioVinc has developed a novel bisphosphonate-tagged PET imaging strategy which we have shown to more thoroughly image bone disease including earlier bone effects of disease than current PET probes of other diagnostic tools. In this STTR R41 application we propose 2nd generation 18F-BP-PET imaging probes to provide breast cancer patients, a more sensitive measure of bone metastases prompting them to take advantage of new treatment strategies known to improve survival in this group. It is our goal to show that these innovative BP-PET probes can overcome some of the disadvantages of current imaging strategies for BC and provide earlier diagnosis of the bone metastases. Our innovative chemistry design offers rapid preparation (within one 18F half-life) of the proposed PET probes. Cold chemistry will be performed at the BioVinc laboratories by Dr. Frank Ebetino and the team, and then elaborated for radiochemistry requirements together with Drs. Kai Chen and Charles McKenna?s group at USC. All radiochemistry, including in situ cyclotron generation of the radioisotope 18F, as well as the in vivo animal studies and PET imaging will be performed under Dr. Kai Chen?s direction at the USC Molecular Imaging Center. We will use 18F-NaF probes as a control imaging agent in an orthotopic rodent model of breast cancer which reliably results in related bone metastases and compare them with our best novel probe for the detection of early changes in the bone due to disease. These proof of concept studies will position our research for rapid translational development in a subsequent Phase II STTR program.